Editorial

A Policy of Preemption: The Timing of Renal

Replacement Therapy in AKI
F. Perry Wilson

Clin J Am Soc Nephrol 9: 15101512, 2014. doi: 10.2215/CJN.07210714

Beliefs about when to initiate dialysis in patients with

AKI are passionately held by nephrologists, and are
on the wholeunsupported by reliable evidence. Indeed, it may be the very lack of high-quality evidence
that gives rise to such impassioned belief systems. It is
commendable that the nephrology community has recognized that addressing this lack of evidence should
be a major target of research (1). Unfortunately, this
research effort has been hindered by a lack of consensus on exactly what the timing issue is.
Two main issues hamper research in this area. The
rst is the tendency for researchers to cast the clinical
question in the context of early versus late dialysis.
This thinking inaccurately parallels efforts to dene the
appropriate initiation of dialysis in the CKD population. In advanced CKD, there is a sense (though it may
be misplaced) of the inevitability of dialysis. In that
setting, the question of whether to start early, perhaps
with an eGFR.10 but ,15 ml/min per 1.73 m2, versus
later, has intuitive appeal (2). In AKI, however, dialysis
may not be inevitable. Indeed, a recent study of post
cardiac surgery patients revealed that of those who
achieve AKI Network stage 1, only 12% progressed
to a higher stage, and of those only 33% went on to
receive dialysis (3). Thus, the decision to not initiate
dialysis does not merely put off the therapy for some
period of time; it may obviate the therapy entirely. Any
study that attempts to address the timing question
must therefore vociferously acknowledge that patients
who do not receive dialysis early may recover, or
die, without ever receiving dialysis late.
The second major issue is a lack of consensus over
what the denition of early is. Studies using RIFLE, AKI
Network, or Kidney Disease Improving Global Outcomes AKI severity scores have, in general, favored
initiation of RRT in the lower stages (4,5). Studies examining time from intensive care unit (ICU) admission
are more varied but seem to suggest a benet to initiation earlier in the ICU course (68). Data from the Program to Improve Care in Acute Renal Disease study
suggests that outcomes of RRT are superior when the
therapy is initiated at a lower BUN (9), although other
cohorts have not found a similar relationship (10). Perhaps revealing the critical nature of the denition of
early, an analysis of the Beginning and Ending Supportive Therapy for the Kidney study revealed that
patients who received RRT earlier relative to ICU
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Copyright 2014 by the American Society of Nephrology

admission fared better than those who received RRT

later. However, when this same population was stratied along the median creatinine at initiation, those
initiated at a higher creatinine had improved outcomes. Stratication by BUN had no effect (11).
In this issue of CJASN, Vaara et al. (12) shed light on
the timing question by dening a set of classic indications for RRT in AKI, including hyperkalemia, acidosis, and volume overload. Using data from the
FINNAKI study (13), a prospective, multicenter ICU
cohort study in which 33.7% of 2901 patients developed AKI, the authors identify four groups of individuals: those who received RRT within 12 hours of
developing conventional indications, those who received RRT .12 hours after developing conventional
indications, those who received RRT before conventional indications, and a propensity-matched group
of individuals who never received RRT. In terms of
90-day mortality, pre-emptive RRT appeared to be
the most effective treatment strategy (the mortality
rate was 26.9% compared with 48.5% among those
who received RRT for conventional indications).
Prior studies have been limited by the absence of a
control group. As mentioned earlier, the salient question is not whether dialysis should be initiated early or
late but rather early or not early. This requires the
identication of a group of individuals who could reasonably receive dialysis, but didnt: a tall order for any
observational cohort. In the absence of an adequate
control, we must constantly wonder if the early group,
by whatever denition, actually needed dialysis at all.
Indeed, if we imagine a world in which all hospitalized patients receive dialysis on admission, we would
expect outcomes to be much better than the current
state of affairs where only the most ill patients receive
the therapy.
Vaara et al. use a propensity scorebased matching
strategy to overcome this limitation, a technique employed by a few other groups, including our own
(14,15). While we did not nd a benet to early initiation of dialysis (rather, we found that dialysis was preferable to no dialysis when initiated among those with
higher serum creatinine concentrations), we did not
use the same denition of early.
In the current manuscript, the classic indications
dened by Vaara et al. are appealing in their breadth,
but they may not translate easily into clinical practice.

Yale University School

of Medicine, New
Haven, Connecticut
Correspondence:
Dr. F. Perry Wilson, Yale
University School of
Medicine, 60 Temple
St, 6th Floor, Suite 6C,
New Haven, CT
06510. Email: Francis.
p.wilson@yale.edu

www.cjasn.org Vol 9 September, 2014

Clin J Am Soc Nephrol 9: 15101512, September, 2014

Indeed, when confronted with a patient with AKI, classic

indications may already exist (the median time from ICU
admission to RRT indication was 0.5 hours). If we are lucky
enough to nd a patient with AKI and no classic indications,
we would be forced to base our dialysis decision on whether
we believe this patient might have similar properties to
those that were used to create the propensity-matched cohort.
Vaara et al. do not imply, of course, that all ICU patients with
AKI should be dialyzed, nor do they identify specic factors
(outside of classic indications) that may be reasonable indications. Moving forward, though, we must improve our ability
to choose who should receive this therapy.
A randomized trial is an appealing solution to this problem, and several attempts have been made; however, these
were underpowered to detect clinically relevant outcomes
(1618). There exist two active trials of dialysis timing in
AKI. The Standard versus Accelerated Initiation of RRT in
AKI (STARRT-AKI) trial has enrolled 100 critically ill patients with a doubling of serum creatinine and oliguria or an
elevated plasma neutrophil gelatinaseassociate lipocalin
level at 12 centers across Canada (19). Participants were
randomly assigned to receive RRT within 12 hours of fullling criteria or to usual care. While the primary outcome
was protocol adherence, the study will also examine 90-day
mortality in both groups. The Initiation of Dialysis Early
Versus Delayed in the Intensive Care Unit (IDEAL-ICU)
study plans to enroll 864 patients with septic shock meeting
RIFLE stage F across 24 ICUs in France (20). Patients will be
randomly assigned to receive RRT within 12 hours of meeting eligibility criteria or to RRT 4860 hours later. Although
the investigators have operationalized a denition of renal
recovery that will allow patients randomly assigned to the
delay group to avoid the treatment, the clear preference is
that dialysis be performed in most trial participants.
These trials may nally shed light on the bedeviling timing question, but they are really only a beginning. STARRTAKI, while novel in its use of a biomarker as a potential
inclusion criteria, is underpowered to detect signicant outcome differences in the two groups, and (by enrolling individuals with only a doubling of creatinine) may have a
signicant nondialysis rate in the control group. Conversely, the IDEAL-ICU study seems to demand that all patients
receive some type of RRT, which may not follow clinical
practice in which a watchful waiting approach is commonly
used (21).
When the decision to start RRT is ambiguous, I am often
asked why not. Indeed, the overarching trend over time
seems to be toward earlier and more continuous dialysis
(22). This question speaks to a misunderstood risk-benet calculus. Like all clinical decisions, the decision of whether to
initiate dialysis depends on an appropriate assessment of
the risks and benets of the therapy. But given the paucity
of randomized trials of dialysis in AKI, we do not have reliable
estimates of risk. Instead, we rely on a general intuition that
the benet of RRT is (for some patients at least) obvious and
the risk is minimal. It is possible that we are harming patients
with RRT, through either the induction of hypotension or exposure to foreign materials such as catheters and the dialysis
membrane itself (23,24). But these risks are often minimized
when the discussion of dialysis initiation is breached. Its clear
that this type of thinking will increase resource utilization and
costs, especially in the critically ill (25).

Editorial: Timing of RRT in AKI, Wilson

1511

There seem to be three approaches available at this point:

(1) Perform an extremely large clinical trial, adequately
powered to detect outcomes of clinical import, such as mortality, and with enough patients to perform rational subgroup analyses employing various timing criteria; (2)
perform multiple smaller clinical trials with extremely carefully dened inclusion criteria; and (3) reconsider our denition of AKI. Although they arent ready for broad clinical
use, biomarker panels may provide the best window into
the physiology of AKI and are increasingly being studied
(2628). Beyond biomarker assays, simply improving prediction rules based on readily available clinical data may
allow us to identify a population likely to progress, thus
obviating the concern that early RRT will inevitably give
treatment to those who might never require it.
Full disclosure: I believe that prompt and prophylactic
initiation of RRT is benecial for certain patients. Unfortunately, I am not sure who those patients are. I remain concerned that the biased evidence favoring early RRT may be
putting some patients in harms way who would otherwise
recover on their own.
Disclosures
None.
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Published online ahead of print. Publication date available at www.
cjasn.org.
See related article, Timing of RRT Based on the Presence of
Conventional Indications, on pages 15771585.